Pancreatic carcinoma is one of the deadliest forms of cancer, and one that is very difficult to treat with conventional chemotherapeutic regimens. As such, the development of new and innovative therapeutic approaches is necessary. The goal of this proposal is to explore the novel possibility that co-suppression of the replicative MCM helicase complex can enhance the anti-proliferative effects of chemotherapeutic agents used in pancreatic cancer treatment. Recent published studies have shown that co-suppression of MCM subunits increases the cytotoxic effects of drugs that produce stress during S-phase (e.g., aphidicolin and hydroxyurea). Unfortunately, these intriguing studies have been limited to non-clinically relevant systems, particularly with regard to pancreatic cancer treatment. We present preliminary studies showing that the MCM co-suppression concept does indeed have the potential for direct clinical applicability. Using these precedents from our own studies, we propose to extend these concepts to pancreatic cancer treatment applicability. We will determine if co-suppression of members of the MCM complex can increase the chemosensitivity of two drugs used for pancreatic cancer treatment, gemcitabine and 5-FU. Complementary to this, we will also use an innovative approach to determine if loss of the ATPase catalytic function of MCM subunits (and of which subunits) is sufficient to increase drug sensitivity. These exploratory studies will use innovative approaches to provide important information for three highly novel concepts related to pancreatic cancer treatment: (a) will serve as a proof of principle that MCM co-suppression can indeed increase the efficacy of current pancreatic cancer drug regimens, (b) will offer justification for future drug development efforts aimed at inactivating MCMs, and (c) will indicate whether the ATPase cleft of MCMs should serve as the focus for drug development aimed at enhancing clinical management of pancreatic cancer patients. PUBLIC HEALTH RELEVANCE: Pancreatic carcinoma is one of the deadliest forms of cancer, and one that is highly resistant to most current forms of chemotherapeutic treatment. Thus, the development of new and innovative therapeutic approaches is necessary. The goal of this proposal is to explore the novel possibility that co-suppression of proteins involved in basic aspects of copying our chromosomes can enhance the anti-tumor effects of chemotherapeutic agents used in pancreatic cancer treatment. Success with this proof of principle study will support the future development of novel drugs that will enhance our ability to control this disease.